Efficacy of EGFR‐TKIs with or without upfront brain radiotherapy for <i>EGFR</i>‐mutant NSCLC patients with central nervous system metastases

Saida, Yu; Watanabe, Satoshi; Abe, Tetsuya; Shoji, Shuichi; Nozaki, Kohei; Ichikawa, Kosuke; Kondo, Rie; Koyama, K.; Miura, Satoru; Tanaka, Hiroshi; Okajima, Masaaki; Tomita, Masaki; Ishida, Takashi; Tsukada, Hiroki; Makino, Masato; Iwashima, Akira; Sato, Kazuhiro; Matsumoto, Naoya; Yoshizawa, Hirohisa; Kikuchi, Toshiaki

doi:10.1111/1759-7714.13189

Cited by 11 publications

(12 citation statements)

References 41 publications

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“…EGFR-TKIs are the most representative class of targeted therapies. Compared with traditional chemotherapy, EGFR-TKIs effectively treat advanced NSCLC with EGFR mutations and significantly prolong the OS of those patients [23][24][25]. However, the application of EGFR-TKIs also has some certain limitations.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor size was measured every alternate day. Tumor volume (V) was calculated using the following formula: Volume (mm 3 ) = (Length × Width 2 ) × 0.5 [24] After 4 weeks, the mice were injected with Barbiturate at 100 mg/kg for euthanasia and the tumors were harvested and weighed. The tumors isolated from mice were then preserved in 4% paraformaldehyde at 4°C until future analysis.…”

Section: In Vivo Studymentioning

confidence: 99%

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EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells

Gong

Yin

et al. 2020

BMC Cancer

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Background Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells. Methods The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting. Results EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo. Conclusions These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: In Vivo Studymentioning

confidence: 99%

EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells

Gong

Yin

et al. 2020

BMC Cancer

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“…Tumor recurrence and metastasis present marked challenges to clinicians and severely affect the prognosis of patients. Approximately prolong OS of patients [29][30][31] . However, the application of EGFR-TKIs also has some certain limitations.…”

Section: Discussionmentioning

confidence: 99%

Ezh2 Inhibitors Reverse Resistance to Gefitinib in Primary Egfr Wild-type Lung Cancer Cells

Gong

Yin

et al. 2020

Preprint

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Background: Lung cancer is the leading cause of cancer-related death worldwide. Non–small-cell lung cancer (NSCLC) is the most common type of lung cancer. Traditional anticancer therapies involving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) have been proven beneficial in the treatment of patients with EGFR mutations. However, patients with EGFR wild-type NSCLC usually fail to respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2), a key molecule of the PRC2 complex, plays an important role in epigenetic regulation and is overexpressed in various tumors. EZH2 inhibitors sensitize various types of tumor cells to antitumor drugs. Therefore, this study aimed to investigate whether the EZH2 inhibitors GSK343 and DZNep, whencombined with gefitinib, can reverse EGFR-TKI resistance in EGFR wild-type NSCLC. Methods:EZH2 expression was evaluated using the RNA sequencing dataset of NSCLC patients (502 lung squamous cell carcinoma cases including 49 paracancerous lung tissues and 513 lung adenocarcinoma cases including 59 paracancerous lung tissues) from The Cancer Genome Atlas (TCGA). We simultaneously also verified EZH2 expressionin 40 NSCLC samples and their corresponding paracancerous lung tissues from our institution via quantitative PCR. The lung adenocarcinoma cell lines A549 and H1299 were treated with EZH2-specific small interfering RNA or EZH2 inhibitors and subjected to analyses of cell viability and apoptosis as well as of EGFR pathway protein expressions by western blotting. Results: EZH2 was upregulated in human NSCLC tissues and was correlated with poor prognosis in patients with lung adenocarcinoma based on data from both TCGA and our institution. Both EZH2 inhibitors sensitized A549 and H1299 cells to gefitinib and suppressed cell viability and proliferation in vitroby downregulating the phosphorylation of EGFR and AKT and inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted stronger inhibitory effects on tumor activity, cell proliferation, and cell migration than single drug administration in vitro and in vivo.Conclusion: Co-administration of EZH2 inhibitors with EGFR-TKIs may be feasible for the treatment of EGFR wild-type NSCLC in patients who refuse traditional chemotherapy.

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“…70 to 48 months. 35,49,51,52,54,56,58,62,102 EGFR: epidermal growth factor receptor; iPFS, intracranial progression-free survival; RT, radiotherapy; TKI, tyrosine kinase inhibitor took first-line TKI alone while 12 underwent LCT plus TKI treatment (oligo-metastasis with ≤3 metastases: 8; with >3 metastases: 4). The LCT regimen included SBRT or hyper-fractionated RT for 11 patients and surgery for 1 patient.…”

Section: Rt To Spine/bone Metastasesmentioning

confidence: 99%

“…However, TTF, CNS‐PFS, and OS were similar between the upfront SRS and WBRT treatment groups. 49 Chen YH reviewed 134 treatment‐naïve EGFRm NSCLC patients who received first‐ or second‐generation EGFR TKIs (erlotinib: 49; gefitinib: 62; and afatinib: 23). Thirty‐eight (29.1%) of these patients underwent brain RT before disease progression, and achieved significant improvements in iPFS.…”

Section: Brain Rt Combined With Tkimentioning

confidence: 99%

EGFR‐mutated stage IV non‐small cell lung cancer: What is the role of radiotherapy combined with TKI?

Liu

et al. 2021

Cancer Medicine

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Lung cancer has the highest morbidity and mortality. 1 Epidermal growth factor receptor (EGFR) mutations are more prevalent in Asian population than in non-Asian patients, 2,3 which are more likely to have brain metastasis than wild-type counterpart. 4,5 In China, EGFR mutations comprise the largest proportion of driver mutations in lung adenocarcinoma, with a frequency of 63.1%, 6 substantially higher than the 17% observed in the USA. 7 EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line treatment option for advanced or metastatic non-small cell lung carcinoma (NSCLC) patients harboring TKI-sensitive EGFR mutations, and confer a greater progression-free survival (PFS) benefit than treatment with cytotoxic chemotherapy. [8][9][10][11][12] Compared with its wild-type counterpart, EGFRm NSCLC is more aggressive and has a higher likelihood of metastasizing to the brain and bone. 13 The resistance to TKI remains inevitable and the role of radiotherapy

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Efficacy of EGFR‐TKIs with or without upfront brain radiotherapy for EGFR‐mutant NSCLC patients with central nervous system metastases

Cited by 11 publications

References 41 publications

EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells

EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells

Ezh2 Inhibitors Reverse Resistance to Gefitinib in Primary Egfr Wild-type Lung Cancer Cells

EGFR‐mutated stage IV non‐small cell lung cancer: What is the role of radiotherapy combined with TKI?

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